Apolipoprotein E receptor 2 (APOER2 or LRP8) is a post-synaptic transmembrane protein that mediates a signaling cascade initiated by the binding of ligands including ApoE and Reelin. APOER2 has been found to protect against loss of coricospinoneurons during normal aging. Following ligand binding, APOER2 interacts with PSD-95, a post-synaptic density protein important for synapse formation and function. This interaction activates the src-family of kinases, ultimately leading to phosphorylation and activation of NMDA receptors. The interaction between PSD95 and APOER2 requires 59 amino acids that are encoded by the alternatively spliced exon 19. APOER2 protein isoforms that lack exon 19 act as dominant negative inhibitors and cause defects in long-term memory storage and spatial learning. The antagonizing activities of the two alternatively spliced forms of APOER2 may suggest a regulatory role in signaling. Given the role of the active form of APOER2 in memory and learning, any disruption in the alternative splicing of this transcript could disrupt signaling and lead to learning and memory defects similar to those seen in Alzheimer's Disease. Indeed, Reelin signaling through these receptors has been shown to be required for critical processes in the developing and adult brain including neuronal migration, dendritic development and synaptic plasticity.
Antisense compounds have been used to modulate target nucleic acids. Antisense compounds comprising a variety of chemical modifications and motifs have been reported. In certain instances, such compounds are useful as research tools, diagnostic reagents, and as therapeutic agents. In certain instances antisense compounds have been shown to modulate protein expression by binding to a target messenger RNA (mRNA) encoding the protein. In certain instances, such binding of an antisense compound to its target mRNA results in cleavage of the mRNA. Antisense compounds that modulate processing of a pre-mRNA have also been reported. Such antisense compounds alter splicing, interfere with polyadenlyation or prevent formation of the 5′-cap of a pre-mRNA.
Certain antisense compounds have been described previously. See, for example, United States Patent Application Publication No. 2014/0114057 and published International Patent Application No. WO 2008/049085, which are hereby incorporated by reference herein in their entirety.